The purpose of this K23 application is to promote my career development in patient-oriented translational research and to facilitate successful transition into an independent investigator in the field of cardiovascular disease pharmacogenomics. Coronary heart disease (CHD) is the leading of mortality in the United States accounting for approximately 1 in 5 deaths. Aspirin as part of a dual antiplatelet therapy (DAPT) regimen significantly improves cardiovascular outcomes in patients with acute coronary syndrome and/or undergoing percutaneous coronary intervention (PCI). However, there is great interindividual variation in platelet response to aspirin, and patients with higher on-treatment platelet reactivity have increased risk of experiencing an ischemic event. This interindividual variation in response is the likely reason why the optimal dose of aspirin when used alone or in combination with other antiplatelet agents is highly controversial. While heritability estimates suggest that genetic factors are an important determinant of aspirin response, candidate gene approaches have failed to identify variants that are reproducibly associated with aspirin response. Recently, using a genome-wide association approach, we identified a common single nucleotide polymorphism (rs12041331) in the platelet endothelial aggregation receptor 1 (PEAR1) gene that contributes substantially to variability in platelet reactivity during DAPT. Furthermore, DAPT-treated PCI patients carrying the risk allele had a 2 to 4-fold decrease in survival at 1 year of follow-up, and aspirin-treated stable coronary artery patients had a 2-fold increase in the rate of myocardial infarction. These associations were not observed in the absence of aspirin administration. We hypothesize that PEAR1 genotype influences aspirin response and is a determinant of optimal aspirin dose. This project aims to: 1) assess the effect of aspirin dosing (81, 162, or 324 mg) on agonist-stimulated ex-vivo platelet aggregation by PEAR1 rs12041331 genotype in healthy Amish individuals (20 per genotype group), and 2) evaluate the interaction between PEAR1 rs12041331 genotype and aspirin dose (81 vs. 324 mg) on 1-year survival in approximately 1,400 PCI patients recruited as part of the PGRN-funded Pharmacogenomics of Anti-Platelet Intervention 2 (PAPI-2) Study. These studies will contribute to our knowledge regarding the genetic underpinnings and mechanisms underlying aspirin resistance as well as optimal aspirin dosing. Given the impact of aspirin therapy on primary and secondary prevention of adverse cardiovascular events, this study has important health implications since 20 - 60% of individuals carry at least 1 copy of the PEAR1 rs12041331 minor allele. Understanding drug response variability in patients taking anti- thrombotics is critical for optimizing cardiovascular pharmacotherapy and ultimately patient outcomes. PUBLIC HEALTH RELEVANCE: Aspirin as part of a dual antiplatelet therapy regimen is the standard of care for preventing adverse cardiovascular outcomes in patients with acute coronary syndrome and/or undergoing percutaneous coronary intervention. Given the wide variability of platelet function and clinical outcomes in response to aspirin therapy, it is importnt to identify the factors that cause dose-response variability and to optimize antiplatelet treatment based on knowledge of these factors. The proposed study will help guide physicians in choosing the most appropriate antiplatelet therapy in the context of PEAR1 genotype, a newly discovered and potentially important genetic contributor to aspirin resistance.